Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage

Abstract

BackgroundEarly brain injury (EBI) is considered a major contributor to the high morbidity and mortality associated with subarachnoid haemorrhage (SAH). Both of sterile inflammation and apoptosis are considered the important causes of EBI. Recently, it was confirmed that thioredoxin-interacting protein (TXNIP) not only participates in inflammatory amplification but also stimulates the apoptosis signalling cascade pathway. However, whether the effects of TXNIP influence the pathogenesis of SAH remains unclear. Here, we hypothesize that TXNIP activity induced by endoplasmic reticulum stress (ER stress) may contribute to the pathogenesis of EBI through pro-inflammatory and pro-apoptotic mechanisms.MethodsA total of 299 male Sprague–Dawley rats were used to create SAH models. Resveratrol (RES, 60 mg/kg) and two TXNIP small interfering RNA (siRNA) were used to inhibit TXNIP expression. The specific inhibitors of ER stress sensors were used to disrupt the link between TXNIP and ER stress. SAH grade, neurological deficits, brain water content and blood–brain barrier (BBB) permeability were evaluated simultaneously as prognostic indicators. Fluorescent double-labelling was employed to detect the location of TXNIP in cerebral cells. Western blot and TUNEL were performed to study the mechanisms of TXNIP and EBI.ResultsWe found that TXNIP expression significantly increased after SAH, peaking at 48 h (0.48 ± 0.04, up to 3.2-fold) and decreasing at 72 h after surgery. This process was accompanied by the generation of inflammation-associated factors. TXNIP was expressed in the cytoplasm of neurons and was widely co-localized with TUNEL-positive cells in both the hippocampus and the cortex of SAH rats. We discovered for the first time that TXNIP was co-localized in neural immunocytes (microglia and astrocytes). After administration of RES, TXNIP siRNA and ER stress inhibitors, TXNIP expression was significantly reduced and the crosstalk between TXNIP and ER stress was disrupted; this was accompanied by a reduction in inflammatory and apoptotic factors, as well as attenuation of the prognostic indices.ConclusionsThese results may represent the critical evidence to support the pro-inflammatory and pro-apoptotic effects of TXNIP after SAH. Our data suggest that TXNIP participates in EBI after SAH by mediating inflammation and apoptosis; these pathways may represent a potential therapeutic strategy for SAH treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0878-6) contains supplementary material, which is available to authorized users.

MCC950, the Selective Inhibitor of Nucleotide Oligomerization Domain-Like Receptor Protein-3 Inflammasome, Protects Mice against Traumatic Brain Injury

“…In different disease models, MCC950 has provided conspicuous protection either in CNS disease models (i.e., Alzheimer's disease [AD] 27 or systemic disorders like diabetic vascular dysfunction). [28][29][30][31] Here, we specified that MCC950 could also alleviate TBI and the consequent proinflammatory and, in particular, proapoptotic signals in the perilesional area.…”

“…Extensively studied for its contribution to insulin resistance and oxidative stress, TXNIP directly associates with NLRP3 and induces inflammasome oligomerization and activation and modulates the expression of various cytokines and proapoptotic signals. 25,29,45,46 TXNIP has been also found be upregulated in response to brain injury coincident with inflammasome activation. 47 Presumptively, this takes place downstream to reactive oxygen species (ROS) release, which, in turn, promotes TXNIP expression trough transcription factor forkhead box O3 (FoxO) in TBI brains.…”

Aggf1 attenuates neuroinflammation and BBB disruption via PI3K/Akt/NF-κB pathway after subarachnoid hemorrhage in rats

“…Aneurysmal subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease with a high rate of mortality and disability [ 1 ]. Neuroinflammation and blood-brain barrier (BBB) disruption have been recognized as important pathological processes in early brain injury (EBI) after SAH [ 2 – 4 ].…”

Melatonin Upregulates Nuclear Factor Erythroid-2 Related Factor 2 (Nrf2) and Mediates Mitophagy to Protect Against Early Brain Injury After Subarachnoid Hemorrhage

“…In addition, several recent studies have demonstrated that TXNIP mediates neuron apoptosis and inflammation during post-SAH EBI, while ER-stress-induced suppression in TXNIP expression could lead to reduced expression of some prognostic indicators and inhibited cell apoptosis and inflammation. Therefore, it was suggested that the suppression of TXNIP may become a potential therapeutic strategy for the treatment of SAH [ 12 ].…”

“…In particular, melatonin has been reported to protect the brain against post-SAH injury [ 17 ]. For example, it was found that the administration of melatonin could regulate the nuclear factor erythroid-2 related factor 2 (Nrf2) signaling pathway to reduce ER stress, which is considered a key contributor to post-SAH EBI [ 12 , 18 – 20 ]. In this study, we established an animal model of SAH and subsequently gave melatonin treatment to SAH animals.…”